A specialized nanoparticle filled with an RNA-based cancer therapy can successfully target human cancer cells and silence the target gene, according to results from an early clinical trial. The research, published today in the journal Nature, is the first to demonstrate this type of tissue targeting and gene-silencing in humans. Researchers haven't yet revealed the clinical effects of the treatment.

"It's a very exciting paper," says Phillip Sharp, an MIT professor who won the 1993 Nobel Prize in medicine for his work on RNA splicing. "It's a statement that we are in this stage in the field [where we're] beginning to use these particles to treat people."

Getting inside: Nanoparticles (black spheres) carry a molecular marker on their surface that engages receptors on a cancer cell’s surface, allowing the nanoparticles to be taken into the cell. Here, the nanoparticles can be seen both entering and inside the cell.

Since the discovery 12 years ago that double-stranded RNA can silence genes in a targeted manner, researchers have hailed the technique, known as RNA interference (RNAi), as a powerful approach to creating new and potent medicines. Indeed, the mechanism garnered its discoverers, Stanford University's Andrew Fire and Craig Mello of the University of Massachusetts Medical School, the 2006 Nobel Prize in medicine. The trouble is, getting the therapeutic RNA to the right cells has proven to be a sticky challenge. When injected on their own, so-called small interfering RNAs (siRNAs) are quickly filtered out by the kidneys, and researchers have struggled to design particles that carry their contents to target cells with enough specificity, or that don't cause toxicity or elicit an immune reaction from the body. So far, a handful of clinical trials have tested the ability of siRNAs delivered directly into the eye or the lung to treat macular degeneration or lung infection caused by respiratory syncytial virus. Because these organs are easily accessible, the therapy was administered directly to the tissue using naked RNA. The new trial, however, is the first to administer the RNA therapy systemically into the body, using specialized particles that protect the RNA while in the bloodstream and target it directly to cancer cells.

The researchers developed a nanoparticle carrying a molecular marker that binds to the surface of cancer cells, triggering the cells to absorb it. The siRNA carried within the particle was designed to silence a gene called ribonucleotide reductase M2 (RRM2), which regulates DNA synthesis and repair and is known to be an anticancer target. Because it was the first trial using targeted RNAi delivery for cancer, says Mark Davis, a professor of chemical engineering at Caltech and the study's lead author, "we wanted to choose a gene that was suspected to be hugely upregulated in a broad spectrum of cancers" in order to increase the likelihood of being able to observe the novel therapy's effect.

The researchers analyzed biopsy samples from three melanoma patients in the trial who had received different doses of the therapy. They tracked the particles in the different samples, finding that the amounts they could see in the tumor cells correlated with the doses the patients received. "That's the first time anyone has seen that for any kind of particle delivery system, whether it's a liposome, a nanoparticle, or anything," says Davis. They also pulled out samples of mRNA cleaved exactly where the siRNA's were designed to cut, showing that the RNAi did its job the way it was expected to. The study does not discuss the clinical effects of the treatment on the melanoma patients in the trial; that data, says Davis, will be presented at the meeting of the American Society of Clinical Oncology in early June. The trial was sponsored by Calando Pharmaceuticals, a California-based startup founded by Davis that is developing nanoparticle-based siRNA therapies for cancer.

The trial is a promising start, say researchers, but much remains to do before such therapies are truly ready for clinical use. "It's a small but important first step," says Judy Lieberman, a professor of pediatrics at Harvard University working on RNAi delivery. "Getting delivery into a peripheral tumor in the skin is very good news." She cautions, though, that it's difficult to draw conclusions from just three patients. "I don't think you can make a dose-dependent statement based on three samples." Also, she notes, the authors didn't report the therapy's effects on molecular features in the tumor cells themselves, such as cell proliferation or apoptosis.

"There's much more data to be collected," says Sharp, who was also a cofounder of and remains a scientific advisor to Alnylam Pharmaceuticals, a biotech company developing RNAi therapeutics. "What's so hard about this set of data is, yes, they see some nanoparticles there, but is it enough?" Indeed, notes Mark Kay, director of the Program in Human Gene Therapy at Stanford University, past work suggests that even when a drug makes it into the correct cell, "a large proportion of it doesn't go into a biologically active compartment" where it can fulfill its therapeutic task. And ultimately, Kay says, "what is still missing--not just from this study but from all studies--is [demonstrating] efficacy of RNAi to treat diseases."